c-MET is a receptor tyrosine kinase (RTK) encoded by human chromosome 7p and activated via its natural extracellular ligand hepatocyte growth factor (HGF) or activated in the absence of HGF when overexpressed or mutated. c-MET is found mutated in a variety of solid tumors (Ma, P. C. et al. Cancer Metastasis (2003) 22: 309). Mutations in the tyrosine kinase domain are associated with hereditary papillary renal cell carcinomas (Schmidt, L. et al. Nat. Genet. (1997)16: 68; Schmidt, L. et al. Oncogene (1999) 18: 2343), whereas mutations in the sema and juxtamembrane domains are often found in small cell lung cancers (Ma, P. C. et al. Cancer Res. (2003) 63: 6272). Many activating mutations are also found in breast cancers (Nakopoulou, et al. Histopath. (2000) 36(4): 313). The panoply of tumor types for which c-MET mediated growth has been implicated suggests this is a target suited for modulation by specific c-MET small molecule inhibitors.
The TPR-MET oncogene is a transforming variant of the c-MET RTK and was initially identified after treatment of a human osteogenic sarcoma cell line transformed by the chemical carcinogen N-methyl-N-nitro-N-nitrosoguanidine (Park, M. et al. Cell (1986) 45: 895). The TPR-MET fusion oncoprotein is the result of a chromosomal translocation, placing the TPR3 locus on chromosome 1 upstream of a portion of the c-MET gene on chromosome 7 encoding only for the cytoplasmic region. Studies suggest that TPR-MET is detectable in experimental cancers (e.g., Yu, J. et al. Cancer (2000) 88: 1801). Dimerization of the Mr 65,000 TPR-MET oncoprotein through a leucine zipper motif encoded by TPR leads to constitutive activation of the c-MET kinase (Zhen, Z. et al. Oncogene (1994) 9: 1691). TPR-MET activates wild-type c-MET RTK and can activate crucial cellular growth pathways, including the Ras pathway (Aklilu, F. et al. Am. J. Physiol. (1996) 271: E277) and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway (Ponzetto, C. et al. Mol. Cell. Biol. (1993) 13: 4600). Conversely, in contrast to c-MET RTK, TPR-MET is ligand independent, lacks the CBL-like SH2 domain binding site in the juxtamembrane region in c-MET, and is mainly cytoplasmic. c-MET immunohistochemical expression seems to be associated with abnormal β-catenin expression, a hallmark feature of epithelial to mesenchymal transition (EMT) and provides good prognostic and predictive factors in breast cancer patients.
It has recently been reported that sustained signaling through cMET kinase may drive the disease etiology of autozomal-dominant polcystic kidney disease (PKD) (Quin, S. et al. J. Clin. Investigation (2010) 120: 3617-3628). Therefore a c-MET kinase inhibitor finds utility in the treatment of PKD and other related ciliopathies.
In human therapeutics, it is desirable to provide small molecule inhibitors of a protein target within in a protein family which do not cross-inhibit closely related protein family members. These closely related protein family members are often referred to as ‘off-targets’, to distinguish them from the essential target of interest referred to as the ‘on target’ of the inhibitor. A small molecule which inhibits multiple protein family members, while being potent against the target of interest, can be limited in its utility as a human therapeutic due to unintended side effects and toxicities introduced due to the consequences of inhibition of these ‘off targets.’
Protein kinases constitute an important therapeutic protein family. There are approximately 518 human protein kinases. While inhibition of a desired kinase ‘on target’ is desirable for a human therapeutic, it is also desirable in many cases to provide a selective kinase inhibitor which does not substantially inhibit other kinase ‘off targets’ from within this protein family. Monoclonal antibodies are one approach to providing specific inhibitors to a specific kinase without inhibiting ‘off targets.’ Achieving this level of selectivity with small molecule inhibitors, however, is not as easily achievable nor as straightforward. Accordingly, there is a need for kinase inhibitors that are selective for a particular protein kinase.